Hemochorial placentation occurs in many mammalian species including primates and rodents. It ensures the most intimate contact between maternal and embryonic compartments and requires specialized adjustments. Among these adjustments is the need for extensive remodeling of the maternal uterine spiral arteries. Uterine vascular modifications are required for the delivery of nutrients to the fetus. Disruptions in this fundamental process lead to diseases of pregnancy and placentation, and result in impaired nutrient transport to the fetus, including the delivery of oxygen. Hypoxemia leads to a range of disruptive events within the fetus that have potentially long-lasting postnatal impacts on health and disease. Mechanisms controlling uterine spiral artery remodeling remain poorly understood. Central to the vascular remodeling process is a specialized population of trophoblast cells referred to as invasive trophoblast or alternatively as extravillous trophoblast (human). Regulatory processes controlling differentiation and function of the invasive trophoblast cell lineage is the focus of this proposal. The rat is used as an experimental model in this investigation because it exhibits deep intrauterine trophoblast invasion and extensive uterine spiral artery remodeling. These events are remarkably similar to that observed in human placentation. The experimental effort is based on our prior establishment and extensive characterization of in vitro and in vivo models for studying rat hemochorial placentation. Through these efforts we discovered two signaling pathways that promote development of the invasive trophoblast lineage: i) hypoxia/hypoxia inducible factor (HIF); ii) phosphatidylinositol 3-kinase (PI3K)/AKT/FOSL1. In this proposal we utilize the hypoxia/HIF and PI3K/AKT/FOSL1 signaling pathways as guides to mechanisms controlling the development of the extravillous/invasive trophoblast lineage. The proposed research provides an innovative approach to studying hemochorial placentation. Collectively, the research is directed toward elucidating molecular mechanisms underlying physiological processes that ensure appropriate hemochorial placentation. This approach will lead to the identification of conserved regulatory pathways controlling the extravillous/invasive trophoblast lineage, which will create opportunities for new scientific and applied pursuits. PUBLIC HEALTH RELEVANCE: Disorders of hemochorial placentation are a significant human health issue. There is a paucity of knowledge regarding the regulation of trophoblast stem cells, their differentiation into invasive cells that effectively invade into the uterus and restructure uterine spiral arteries, and establish the maternal-fetal interface. Experimental dissection of fundamental mechanisms underlying the derivation of the invasive trophoblast lineage is a key to understanding the etiology of placentation-related diseases and a necessity for establishing appropriate and efficacious diagnostic and therapeutic strategies.